Risk of Delirium With Concomitant Use of Tolterodine and Acetylcholinesterase Inhibitors

To the Editor: Anticholinergic drugs can cause disorientation, confusion, delirium, memory impairment, and obtundation in older patients who may be susceptible to the inhibition of acetylcholine.1 Even in normal, healthy adults, some anticholinergic medications can interfere with attention and learning.2 In the recent article by Maline-Lee et al., tolterodine was shown to have a low incidence of central nervous system (CNS) side effects.3 The relatively low penetration into the CNS, due to the tolterodine's low lipophilicity may account for this. Nevertheless, tolterodine is not free of potential significant CNS side effects, as shown below. We describe three cases of acute anticholinergic-induced delirium by tolterodine in patients taking acetylcholinesterase inhibitors (AChEI) for treatment of dementia. An 82-year-old man with a 3-year history of Alzheimer's disease had been taking donepezil 5 mg at bedtime for 2 months. The patient was ambulatory and was able to feed and dress himself with some assistance. He was prescribed tolterodine for urinary incontinence. Within a week after initiating this drug, the patient became acutely delusional and aggressive. The tolterodine was discontinued and the patient returned to his baseline status within 48 hours. An 82-year-old woman taking rivastigmine 6.0 mg twice a day for Alzheimer's disease had been stable and in an assisted living situation for 3 years. She began taking tolterodine for symptoms of urinary incontinence. Within 1 week, she became agitated and anxious and experienced panic attacks, increased confusion, and frank delusions. She could not be comforted. She was then given two 0.5 mg doses of lorazepam without any improvement. Two days after discontinuing the lorazepam, tolterodine was discontinued, and, within 24 hours, the patients agitation, delirium, and panic attacks subsided. She was maintained on rivastigmine throughout this period. An 82-year-old man with a 10-year history of Parkinson's disease and a 2-year history of dementia had been taking donepezil 10 mg daily for 2 years. After experiencing symptoms of urinary urgency, he was prescribed tolterodine 2 mg twice a day. Within 2 weeks of initiating tolterodine, the patient became progressively disoriented and confused. After experiencing several falls, he was brought to a local emergency department by family members and was seen by one of the authors. In the emergency department, he was combative and disoriented. Serum electrolytes, liver enzymes, urinalysis, and culture were unremarkable. Computed tomography scan was normal except for generalized atrophy. Tolterodine was discontinued, and, within 24 hours, the patient returned to his baseline status. Anticholinergic drugs decrease acetylcholine activity in the brain by blocking cholinergic receptors. Older patients are especially susceptible to drug-induced cognitive impairment because of age-related decrements in acetylcholine. A rapid decrease in acetylcholine activity produced by anticholinergic drugs in the brain of an older patient can result in acute delirium, confusion, disorientation, memory impairment, and obtundation. Anticholinergic drugs such as oxybutynin, atropine, and scopolamine have been known to cause these reactions in older patients, even in patients who do not show signs of clinically apparent dementia. Other classes of drugs with anticholinergic effects such as tricyclic antidepressants may have delirium and other cognitive problems as side effects. In an older patient on AChEI therapy for dementia, the addition of an anticholinergic medication such as tolterodine can be debilitating. Because of their opposing actions, the combination of these two classes of medications presents at least a probable drug-drug interaction in the CNS. Even though their effects on acetylcholine levels in the brain might seem simply to cancel each other out, the anticholinergic action effectively depletes the brain of acetylcholine. In our patients, this drug-drug interaction seemed to precipitate a state of cholinergic neurogenic hypersensitivity similar to that often observed with sudden withdrawal of an AChEI. Furthermore, recent studies have shown that the total burden of anticholinergic drugs, rather than any single event, may determine development of delirium.4 Tolterodine is often promoted as “better tolerated” than other anticholinergic medications. This medication is a competitive muscarinic receptor antagonist with anticholinergic effects and may have some proven selectivity for receptors in the urinary bladder. Although a number of studies have shown a decreased incidence of side effects with tolterodine than with oxybutinin,5 our cases demonstrate that, in patients taking an AChEI for dementia due to a cholinergic deficit, tolterodine can cause a state of clinically significant delirium. Anticholinergic drugs should be used only with extreme caution in older patients. These medications, and tolterodine in particular, should be strictly avoided in dementia patients receiving therapy with an AChEI.